Objective To evaluate the clinical outcomes of three different sealers for one-visit root canal therapy. Methods A total of 362 patients/425 teeth diagnosed as pulpitis were randomly divided into three groups: group A, including 120 patients/121 teeth, treated with zinc oxide engenol(ZOE); group B, including 121 patients/151 teeth, treated with Cortisomol; and group C, including 121 patients/153 teeth, treated with 2Seal easymiX. All the teeth were filled with gutta percha by cold lateral condensation. The post-treatment pain and the one-year successful rate were observed. Results The incidence rate of post-treatment pain in group A (15.7%\[19/121\]) were significantly higher than those in group B (5.3%\[8/151\] , P<0.01) and group C (6.5%\[10/153\], P<0.05); and there was no significant difference between group B and C. The one-year successful rates were not significantly different between group A (94.0%\[110/117\]), B (96.5%\[137/142\]) and C (97.9%\[142/145\]). Conclusion The three kinds of root canal sealers can all achieve satisfactory one-year successful rate in one-visit root canal therapy; moreover, Cortisomol and 2Seal easymiX can also reduce post-treatment pain, making them ideal root canal sealers.